Abstract

Castrate resistant prostate cancer (CRPC) remains the primary cause of mortality for prostate cancer (PCa) patients. Several therapies are currently approved for use against CRPC, consisting mostly of androgen receptor (AR) signaling inhibitors and toxic anti-microtubule chemotherapeutics that do not score long-term durable responses. Recent deep-sequencing analysis studies have elucidated the complex and heterogeneous landscape of CRPC, highlighting the necessity to develop effective targeted therapies against specific CRPC subtypes or therapies effective against numerous subtypes of CRPC. PTEN and p53 are two of the most frequently altered genes in CRPC, and are associated with therapy resistance and a poor clinical prognosis. The objective of this study was to identify and subsequently validate therapeutic targets against models of advanced PCa, specifically in the absence of PTEN and p53. Using non-biased high throughput screening technology, we identified HSP90 inhibitors to be potent and efficacious against a model of PTEN/p53 null PCa. HSP90 is a critical regulator of prostate cancer cell signaling homeostasis, and recently developed second generation compounds targeting HSP90 are effective against genotypically heterogeneous panels of cancer cell lines and have favorable safety parameters in the clinic. Screening results and subsequent validation efforts in vitro identified ganetespib as the most potent HSP90 inhibitor, with efficacy that translated into established human PCa cells lines. Ganetespib also displayed strongly inhibitory activity against PTEN/p53 null progenitor cells, a plastic subpopulation of PCa believed to be partly responsible for therapy resistance. In vivo, ganetespib completely inhibited progression of PIN to invasive adenocarcinoma in the Pten/Tp53 null PCa mouse model, leading to a significant reduction in tumor weight. Expanding from the mouse model to clinically predictive PDX-derived LuCaP models of human PCa, we found that ganetespib displayed a range of activity against a genotypically diverse array of 11 LuCaP organoids ex vivo. Furthermore, the PTEN null/p53 altered LuCaP 136 displayed a robust response to ganetespib in vivo, with ganetespib causing a significant reduction in tumor growth. Mechanistic interrogation in vitro, ex vivo, and in vivo revealed ganetespib induced effects to be multifactorial and model specific, with unifying trends being inactivation of PI3K signaling and modulation of cell cycle regulatory proteins. In all, these data indicate that inhibition of HSP90 is a novel therapeutic to treat advanced PCa via multifactorial perturbation of growth regulatory pathways.